Premarket Approval Supplement Pathway: Do We Know What We Are Getting?

The global medical device industry has dramatically ex-panded in the past 5 years, with the market expected to be valued at more than $228 billion by 2015 as medical devices increase in number, use, and complexity (1). High-risk (class III) devices (those that “support or sustain hu-man life ” [2]) are generally approved by the U.S. Food and Drug Administration (FDA) via a pathway known as “pre-market approval ” (PMA), which uses criteria of safety and effectiveness. However, modifications of PMA devices may be approved by a less rigorous procedure known as “PMA supplement, ” which has substantially fewer evidence re-quirements than an original PMA. Recent events have raised safety concerns for this alternate pathway, and un-derstanding these implications is important for clinicians and policymakers. A PMA supplement is required for a “change affecting the safety or effectiveness of the device for which the ap-plicant has an approved PMA ” (3). Device manufacturers may frequently have improvements or minor changes to approved devices, and PMA supplements allow iterative changes without the need to go through the rigorous PMA process. The need for rapid approval of design improve-ments to marketed devices must be weighed against the possibility of introducing unknown risks to patient health from such modifications, especially because devices often have multiple supplements. In one recent tragic example, the Sprint Fidelis defibrillator lead (Medtronic, Minneap-olis, Minnesota) was recalled after 665 failures and 5 deaths (4). The Fidelis lead had undergone successive changes to the original approved device via several PMA supplements, none of which required clinical data. Because of the cumulative modifications, the devices ultimately marketed as the Fidelis differed substantially from the one originally studied in clinical trials before the PMA supple-ments. Implantations of the Fidelis lead—the safety and efficacy of which were never shown through clinical trials—exploded to 268 000 worldwide until the device was recalled in 2007 because of increased risk for life-threatening lead fractures (5). To this day, caring for more than 150 000 Americans with this lead remains a clinical challenge (6). In a similar heartrending example, from 2002 to 2006